Glycoprotein 130 Receptor Signaling Mediates α-Cell Dysfunction in a Rodent Model of Type 2 Diabetes

Abstract

Dysregulated glucagon secretion accompanies islet inflammation in type 2 diabetes. We recently discovered that interleukin (IL)-6 stimulates glucagon secretion from human and rodent islets. IL-6 family cytokines require the glycoprotein 130 (gp130) receptor to signal. In this study, we elucidated the effects of a-cell gp130 receptor signaling on glycemic control in type 2 diabetes. IL-6 family cytokines were elevated in islets in rodent models of this disease. gp130 receptor activation increased STAT3 phosphorylation in primary a-cells and stimulated glucagon secretion. Pancreatic a-cell gp130 knockout (agp130KO) mice showed no differences in glycemic control, a-cell function, or a-cell mass. However, when subjected to streptozotocin plus high-fat diet to induce islet inflammation and pathophysiology modeling type 2 diabetes, agp130KO mice had reduced fasting glycemia, improved glucose tolerance, reduced fasting insulin, and improved a-cell function. Hyperinsulinemic-euglycemic clamps revealed no differences in insulin sensitivity. We conclude that in a setting of islet inflammation and pathophysiology modeling type 2 diabetes, activation of a-cell gp130 receptor signaling has deleterious effects on a-cell function, promoting hyperglycemia. Antagonism of a-cell gp130 receptor signaling may be useful for the treatment of type 2 diabetes.Islet inflammation (1,2) and pancreatic a-cell dysfunction (3-6) contribute to hyperglycemia in patients with type 2 diabetes. Pancreatic islets from patients with type 2 diabetes are infiltrated with macrophages (7,8), express elevated proinflammatory cytokines (9,10), and express features of fibrosis (11), consistent with reports from animals and primates with this disease (7,(12)(13)(14)(15)(16)(17)(18). The detrimental effects of inflammation on islet b-cell function were recently confirmed, when the interleukin (IL)-1 receptor antagonist reduced hyperglycemia and improved b-cell insulin secretion in patients with type 2 diabetes (1).Pancreatic a-cell dysfunction is detectable in the early stages of type 2 diabetes, where the inverse relationship between pulsatile insulin and glucagon secretion is lost (19). This dysregulation is associated with relative hyperglucagonemia, which contributes to the development of fasting hyperglycemia associated with frank type 2 diabetes (6). Indeed, inhibition of glucagon action by various means reduces hyperglycemia in rodent models of this disease (5,6).

Genetic Drivers of Pancreatic Islet Function

“…Il6st, also known as glycoprotein 130 (gp130), is the β-subunit of the IL-6 cytokine receptor. A recent report showed that Il6st is required for IL-6-mediated activation of STAT3, and stimulation of glucagon secretion (CHOW et al 2014). Further, α-cell-specific deletion of Il6st resulted in protection from Streptozotocin-induced diabetes (CHOW et al 2014), suggesting that in the context of inflammation that accompanies T2D, Il6st may promote hyperglycemia by stimulating glucagon secretion from α-cells.…”

“…A recent report showed that Il6st is required for IL-6-mediated activation of STAT3, and stimulation of glucagon secretion (CHOW et al 2014). Further, α-cell-specific deletion of Il6st resulted in protection from Streptozotocin-induced diabetes (CHOW et al 2014), suggesting that in the context of inflammation that accompanies T2D, Il6st may promote hyperglycemia by stimulating glucagon secretion from α-cells. Il6st is in the royalblue module, along with transcripts that are significantly enriched for the GO term, "positive regulation of cytokine production".…”

Cellular Signaling Pathways in Insulin Resistance-Systems Biology Analyses of Microarray Dataset Reveals New Drug Target Gene Signatures of Type 2 Diabetes Mellitus

“…The dysregulation and functional aberration of these differential genes has also been studied (Baxter, 2008; Pihlajamäki et al, 2009; Jewell et al, 2010; Jowett et al, 2010; Nitert et al, 2012; Reddy et al, 2012; Chow et al, 2014; Liew et al, 2014; Neglia et al, 2014) in type 2 diabetes progression. The T2DM linked genes including ZEB1, USP16, IL6ST, ASPH, Eif4g1, RBL2, MEF2A, vapB, and SOS2 effect on pancreatic β-cells, peripheral glucose uptake in muscles, the secretion of multiple cytokines, β-cell gene expression, islet cells, β-cells chromatin and proliferation attenuation (Baxter, 2008; Jowett et al, 2010; Nitert et al, 2012; Chow et al, 2014; Liew et al, 2014). The genetic networks extended the analysis of transcripts to predict interactive gene signatures that have role in diabetes pathophysiology.…”

“…Another systems biology approach based on genome wide association studies explored the T2DM pathophysiology and insulin signaling genes (Jain et al, 2013). Similarly, the abnormal secretion of glucagon led to islet inflammation in T2DM and it has been seen the interleukin-6 is involved to stimulate the glucagon secretion (Chow et al, 2014). …”

The regulatory roles of NADPH oxidase, intra- and extra-cellular HSP70 in pancreatic islet function, dysfunction and diabetes

“…On the other hand, the absence of IL6 is associated with decreased expression of iHSP70 in skeletal and cardiac muscle of mice challenged with LPS, although IL-6 seems not to be required for exercise-induced HSP production [134]. In addition, recent work has shown that IL-6 acts on α-cells by binding to GR130 receptors and (via STAT3) thus stimulating glucagon synthesis [135]. What is more, incubation of α-cells with IL-6 protects from cell death induced by a mixture of cytokines [IL-1β, TNFα and interferon γ (IFNγ )], consistent with previous observations under nutrient stress [124].…”